1) Examining the A Disintegrin And Metalloproteinase (ADAM) family in trophoblast biology
A specific focus of my research over the past year has examined the importance of the A Disintegrin And Metalloproteinase (ADAM) protease family member, ADAM12, in directing two cellular processes essential in placentation: cell invasion and cell fusion. Despite exceptionally high levels of ADAM12 expression in placental tissues, prior to my lab’s work, the biological significance of ADAM12 in trophoblast biology was unknown. Building upon my recent findings, my short-term objectives aim to characterize the molecular processes directed by ADAM12 in regulating trophoblast differentiation into invasive and multinuclear cell types.
As the biology of ADAM12-related genes in trophoblast function is unknown, I also aim to examine the importance of multiple ADAM family members in trophoblast biology using a global gene expression approach (see Aim 3 below). These extensive studies will inform us of the key ADAM proteases expressed in specific trophoblast subsets and the key signaling pathways and gene interactions linked to biological processes critical in early placental development (i.e. cell survival, proliferation, motility, cell fusion).
2) Examining the effects of obesity-associated inflammation on the maternal-fetal interface
Within the uterine microenvironment, maternal immune cells play a prominent role in regulating trophoblast function and survival. Abnormal changes in the balance of immune cell populations in utero can alter early placental development and have a direct effect on maternal health, fetal outcome and newborn health. Early stages of uterine arterial remodeling, trophoblast invasion and survival, as well as maternal tolerance of the fetal semi-allograft (half mom, half dad) are controlled by uterine immune cells, which are mainly comprised of decidual natural killer cells (dNKs; 70% of total immune cells), but also have significant numbers of myeloid-derived dendritic cells and macrophages (15%) and subsets of regulatory and effector T cell lymphocytes (10%). Alterations in immune cell composition and/or function at the fetal-maternal interface have major implications in trophoblast fitness and pregnancy outcome.
In healthy pregnancy, dNKs, macrophages and regulatory T lymphocytes (Tregs) adopt an immunoprotective role, limiting pro-inflammatory cytokine production and cytolytic/cytotoxic cellular immunity. However, a shift in balance towards pro-inflammatory cytokine producing immune cells within the uterine microenvironment is associated with impaired trophoblast function and survival, poor pregnancy outcome and compromised fertility. These correlations have been substantiated by experiments in mice showing that depletion of key protective/immunosuppressive immune cells leads to under-remodeled uterine arteries, under-perfused vessels, smaller litter sizes and increased fetal demise. Together, these findings indicate that changes in the uterine immune cell microenvironment may significantly alter early placentation.
In obesity, adipocyte expansion leads to heightened secretion pro-inflammatory factors like TNFa and IL-6 by fat cells (adipocytes), which together drive macrophage activation and contribute to the development of metabolic and immune syndromes. Obesity-associated inflammation is characterized by a subtle shift in the balance between different types of T lymphocytes (effector vs. regulatory), resulting in chronic low-level pro-inflammatory cytokine production, tissue cytotoxicity and apoptosis.
Work in my lab is currently profiling the uterine immune cell make-up in obese pregnant women in early pregnancy using a sophisticated multicolor flow cytometry approach. My lab is especially interested in understanding the importance of CD4+ T helper and immunosuppressive regulatory cells within the uterine environment with a particular focus on their roles in directing trophoblast survival and function.
3) Identifying gene expression differences in subpopulations of trophoblasts in normal and pathological pregnancies
State of the art cell-sorting techniques and an understanding of unique cell surface expression markers on trophoblast subpopulations establishes an attractive method in identifying intrinsic trophoblast-specific genes in causative mechanisms in the development of pregnancy-related disorders. To this end, my lab is characterizing specialized trophoblast subpopulations within the placenta and maternal uterine tissue using state-of-the-art FACS-purification strategies. These studies are designed to answer questions directly related to:
- Critical gene pathways essential in placental development, trophoblast differentiation, and trophoblast progenitor cell homeostasis.
- Determining pathways dysregulated in pregnancy disorders (IUGR pregnancies and preeclampsia) and pregnancies associated with heightened risk of placental dysfunction (obesity).